Abstract
BACKGROUND: Oesophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related deaths worldwide because existing treatments are often insufficient. Therefore, new, reliable biomarkers must be identified. CTSL overexpression is closely associated with tumour progression and poor prognosis. However, the role and mechanism of CTSL as an oncogene in ESCC remain unclear. METHODS: Genome-wide association study (GWAS) data were used for Mendelian randomization analysis to investigate the possible relationships between CTSL and ESCC. The correlation between CTSL expression and prognosis was analysed using GEO, TCGA, and GEPIA data. We compared CTSL expression among the cell types using single-cell sequencing. Correlations between CTSL and the tumour microenvironment, immune cell infiltration, tumour mutational load, immunological checkpoints, and treatment sensitivity in patients with ESCC were investigated. Finally, using mouse models and cellular investigations, we assessed the effects of CTSL on the growth, apoptosis, and metastasis of ESCC tumour cells. RESULTS: CTSL was overexpressed in ESCC and correlated with prognosis. We also discovered its close association with cell immunity, especially with tumour-associated macrophages and immune checkpoints in the tumour microenvironment. CTSL may play a key role in ESCC development by affecting M2 macrophage polarisation. CTSL and the M2 macrophage marker genes showed significant positive correlations. Mendelian randomization analysis confirmed a relationship between CTSL and ESCC. Finally, our in vitro and in vivo experiments demonstrated that CTSL promoted the proliferation and migration of ESCC cells, validating our bioinformatic analysis. CONCLUSION: CTSL emerged as a crucial gene in ESCC that influences patient prognosis and immunity, particularly in association with M2 macrophages. Therefore, targeting or modulating CTSL levels may provide new therapeutic strategies for patients with ESCC.